A Genome-Wide View of the In vitro Response to l-Asparaginase in Acute Lymphoblastic Leukemia

Fine, Bernard M.; Kaspers, Gertjan J.L.; Ho, Minh; Loonen, Anne H.; Boxer, Linda M.

doi:10.1158/0008-5472.291.65.1

Cited by 103Acute Lymphoblastic Leukemia researchAmino Acid Enzymes and MetabolismBiochemical and Molecular Research

A Genome-Wide View of the In vitro Response to l-Asparaginase in Acute Lymphoblastic Leukemia

Fine, Bernard M., Kaspers, Gertjan J.L., Ho, Minh, Loonen, Anne H., Boxer, Linda M.·2005·Cancer Research

DOI 10.1158/0008-5472.291.65.1

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Abstract

To investigate the effect of l-asparaginase on acute lymphoblastic leukemia (ALL), we used cDNA microarrays to obtain a genome-wide view of gene expression both at baseline and after in vitro exposure to l-asparaginase in cell lines and pediatric ALL samples. In 16 cell lines, a baseline gene expression pattern distinguished l-asparaginase sensitivity from resistance. However, for 28 pediatric ALL samples, no consistent baseline expression pattern was associated with sensitivity to l-asparaginase. In particular, baseline expression of asparagine synthetase (ASNS) was not predictive of response to l-asparaginase. After exposure to l-asparaginase, 5 cell lines and 10 clinical samples exhibited very similar changes in the expression of a large number of genes. However, the gene expression changes occurred more slowly in the clinical samples. These changes included a consistent increase in expression of tRNA synthetases and solute transporters and activating transcription factor and CCAAT/enhancer binding protein family members, a response similar to that observed with amino acid starvation. There was also a consistent decrease in many genes associated with proliferation. Taken together, the changes seem to reflect a consistent coordinated response to asparagine starvation in both cell lines and clinical samples. Importantly, in the clinical samples, increased expression of ASNS after l-asparaginase exposure was not associated with in vitro resistance to l-asparaginase, indicating that ASNS-independent mechanisms of in vitro l-asparaginase resistance are common in ALL. These results suggest that targeting particular genes involved in the response to amino acid starvation in ALL cells may provide a novel way to overcome l-asparaginase resistance.

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Genome-wide analysis has shown that no consistent gene expression pattern dictates sensitivity to L-asparaginase.
“In fact, genome-wide analysis has shown that there is no consistent gene expression pattern that dictates sensitivity to L-asparaginase (Fine et al., 2005).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Fine et al., 2005

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Molecular mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia
Tissing, W. J. E. (2006) · RePub (Erasmus University Rotterdam)
Genetic and BiologicalDiversity in TEL-AML1 Positive ALL
Stams, W. A. G. (2005) · RePub (Erasmus University Rotterdam)

Low expression of asparagine synthetase in lymphoid blasts precludes its role in sensitivity to L-asparaginase
Heřmanová, I., Zaliova, M. K., Trka, J., & Starková, J. (2012) · Experimental Hematology · doi:10.1016/j.exphem.2012.04.005 · Cited by 58 · see citing works
Association of Asparagine Synthetase Expression and Sensitivity to L-Asparaginase in Cell Lines and Primary Pediatric Acute Lymphoblastic Leukemia Samples.
Heřmanová, I., Trka, J., & Starková, J. (2009) · Blood · doi:10.1182/blood.v114.22.2738.2738
The mechanism of action of L-asparaginase in childhood acute lymfoblastic leukemia
Heřmanová, I. (2015) · Digital Repository (National Repository of Grey Literature)
Amino Acid Stress Response Genes Promote L-Asparaginase Resistance in Pediatric Acute Lymphoblastic Leukemia
Ferguson, D. C. J., McCorkle, J. R., Dong, Q., Bonten, E. J., Yang, W., Bergeron, B. P., Autry, R. J., Diedrich, J. D., Gocho, Y., Bajpai, R., et al. (2021) · Blood · doi:10.1182/blood-2021-152940 · Cited by 1 · see citing works
Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia
Stams, W. A. G. (2005) · Blood · doi:10.1182/blood-2004-10-3892 · Cited by 86 · see citing works

Authors: Fine, B. M., Kaspers, G. J. L., Ho, M., Loonen, A. H., & Boxer, L. M.
Affiliations: Howard Hughes Medical Institute (US)
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
VA Palo Alto Health Care System (US)
ORCID: Fine, Bernard M.
Kaspers, Gertjan J.L.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2005-01-01
Volume: 65
Issue: 1
Pages: 291-299
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.291.65.1
OpenAlex: W1867192423
Cited by: 103
References: 52
Citations by year: 2025: 3 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 8 · 2014: 11 · 2012: 5
FWCI: 10.44
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: National Institutes of Health (1r01ca092326-01)
National Cancer Institute (CA85129, CA92326, K08CA095563, U01CA085129)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords: L-asparaginase, acute lymphoblastic leukemia, pediatric leukemia, gene expression profiling, asparagine synthetase, drug resistance, tRNA synthetase, amino acid transporters, C/EBP transcription factors, cell proliferation, leukemia cell lines
MeSH terms: Adolescent, Antineoplastic Agents, Asparaginase, Child, Female, Humans, Male, Recurrence, Translocation, Genetic, Genome, Human, Artificial Gene Fusion, Cell Line, Tumor, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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A Genome-Wide View of the In vitro Response to l-Asparaginase in Acute Lymphoblastic Leukemia

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